Pyridopyrazines and the use thereof as kinase inhibitors

ABSTRACT

The invention relates to novel pyrido[2,3-b]pyrazine derivatives of the general Formula I, their preparation and use as medicaments, in particular for the treatment of malignant and other disorders based on pathological cell proliferations

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication Nos. 60/473,935 filed on May 28, 2003 and 60/568,610 filedon May 6, 2004 and German Patent Application No. 103 23 345.8 filed onMay 23, 2003, all of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates to kinase modulators of the pyrido[2,3-b]pyrazinetype and to the preparation and use thereof as medicaments for themodulation of misdirected cellular signal transduction processes, inparticular for influencing the function of tyrosine and serine/threoninekinases and for the treatment of malignant or benign oncoses and otherdisorders based on pathological cell proliferation, such as, forexample, restenosis, psoriasis, arteriosclerosis and cirrhosis of theliver.

BACKGROUND OF THE INVENTION

Activation of protein kinases is a central event in cellular signaltransduction processes. Aberrant kinase activation is observed invarious pathological states. Targeted inhibition of kinases is thereforea fundamental therapeutic aim. The phosphorylation of proteins isgenerally initiated by extracellular signals and represents a universalmechanism for controlling various cellular events such as, for example,metabolic processes, cell growth, cell migration, cell differentiation,membrane transport and apoptosis. The kinase protein family isresponsible for protein phosphorylation. These enzymes catalyse transferof phosphate to specific substrate proteins. Based on the substratespecificity, the kinases are divided into two main classes, the tyrosinekinases and the serine/threonine kinases. Both the receptor tyrosinekinases and the cytoplasmic tyrosine and serine/threonine kinases areimportant proteins in cellular signal transduction. Overexpression ordegradation of these proteins plays an important part in disorders basedon pathological cell proliferations. These include inter alia metabolicdisorders, disorders of the connective tissue and of the blood vessels,and malignant and benign oncoses. In tumour initiation and developmentthey frequently occur as oncogens, i.e. as aberrant, constitutivelyactive kinase proteins. The consequences of this excessive kinaseactivation are, for example, uncontrolled cell growth and reduced celldeath. Stimulation of tumour-induced growth factors may also be thecause of overstimulation of kinases. Development of kinase modulators istherefore of particular interest for all pathogenic processes influencedby kinases.

Pyrido[2,3-b]pyrazine derivatives substituted in position 6 or 7 arewidely used as pharmacologically active compounds and as synthons inpharmaceutical chemistry. For example, the patent WO 99/17759 describespyrido[2,3-b]pyrazines which have in position 6 inter alia alkyl-, aryl-and heteroaryl-substituted carbamates. These compounds are intended tobe used to modulate the function of serine-threonine protein kinases.

The patent WO 04/005472 of White et al. describes inter aliapyrido[2,3-b]pyrazines which are carbamate-substituted in position 6 andwhich, as antibacterial substances, inhibit the growth of bacteria. Anantitumour effect is not described.

Certain diphenylquinoxalines and -pyrido[2,3-b]pyrazines with specificalkylpyrrolidine, alkylpiperidine or alkylsulphonamide radicals on aphenyl ring, which may additionally carry urea or carbamatesubstitutions in position 6 or 7 are described in patents WO 03/084473(Barnett et al.), WO 03/086394 (Bilodeau et al.) and WO 03/086403(Lindsley et al.) as inhibitors of the activity of the serine/threoninekinase Akt. Use of these compounds in the treatment of cancers is given.No defined indication of a biological effect is given for thepyrido[2,3-b]pyrazine example compounds described there. Moreover, thereis a distinct structural difference to the pyrido[2,3-b]pyrazinesaccording to the invention described in this invention.

In addition, the patent WO 03/024448 of Delonne et al. describes amide-and acrylamide-substituted pyrido[2,3-b]pyrazines which also containcarbamates as additional substituents and can be used as histonedeacetylase inhibitors for the treatment of disorders of cellproliferation.

A further publication (C. Temple, Jr.; J. Med. Chem. 1990, 3044-3050)describes in one example the synthesis of a 6-ethylcarbamate-substituted pyrido[2,3-b]pyrazine derivative. An antitumoureffect is neither disclosed nor obvious. The synthesis of furtherderivatives of 6-ethyl carbamate-subsfituted pyrido[2,3-b]pyrazine isdescribed in a publication by R. D. Elliott (J. Org. Chem. 1968,2393-2397). A biological effect of these compounds is neither describednor obvious.

The publication by C. Temple, Jr., J. Med. Chem. 1968, 1216-1218describes the synthesis and investigation of 6-ethylcarbamate-substituted pyrido[2,3-b]pyrazines as potential antimalarialagents. An antitumour effect is neither disclosed nor obvious.

BRIEF SUMMARY OF THE INVENTION

The invention is therefore directed at generating novel compounds whichare suitable as modulators of receptor tyrosine kinases and cytoplasmictyrosine and serine/threonine kinases. Since not all kinases connectedone behind the other in misdirected signal transduction cascades—suchas, for example, in the case of Raf/Mek/Erk—have to be present asoncogenic kinases or as constitutively active enzymes, in this inventionthe non-active kinases will also be considered to be therapeutic targetproteins, i.e. the new compounds can bind both to active and also tonon-active kinases and therefore influence the signal transduction.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found, surprisingly, that novel compounds from thepyrido[2,3-b]pyrazine series which are substituted in position 6 or 7for example by urea, thiourea, guanidine or amidine groups are suitablefor producing medicaments for the modulation of misdirected cellularsignal transduction processes, in particular for influencing thefunction of tyrosine and serine/threonine kinases and for the treatmentof malignant or benign oncoses, such as, e.g. of the breast, prostate,lung, skin and ovaries and other disorders based on pathological cellproliferations. According to this aspect, the present applicationdescribes novel compounds from the pyrido[2,3-b]pyrazine series of thegeneral Formula I

in which the substituents R1-R4 have the following meaning:R1 and R2 may be independently of one another:

-   (i) hydrogen-   (ii) hydroxyl-   (iii) halogen, such as, for example, chlorine or bromine-   (iv) alkyl, where the alkyl radical is saturated and may consist of    1 to 8 C atoms,-   (v) unsubstituted or substituted aryl, where the aryl radical may    have one or more identical or different F, Cl, Br, I, CF₃, CN, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,    NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl,    NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl,    NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH,    S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl,    O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl,    O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH,    O—(CH₂)_(n)—O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl,    OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl,    OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl,    OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl,    OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl,    C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,    CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl,    SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl,    alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, n    can have the value 1, 2 or 3, and the alkyl, cycloalkyl,    heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl,    alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents may    in turn themselves be substituted,-   (vi) unsubstituted or substituted heteroaryl, where the heteroaryl    radical may have one or more identical or different F, Cl, Br, I,    CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl,    NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH,    N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl,    NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl,    NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl,    NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl,    NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl, OH,    OCF₃, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl,    O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,    O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl,    OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl,    OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl,    OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl,    C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,    CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl,    SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl,    alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,    and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl    substituents may in turn themselves be substituted,-   (vii) OR5, where R5 can be alkyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or    alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or    alkylheteroaryl substituents can, for their part, in turn be    substituted,-   (viii) SR6, where R6 can be alkyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or    alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and    heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or    alkylheteroaryl substituents can, for their part, in turn be    substituted,-   (ix) NR7R8, where R7 and R8 can, independently of each other, be    hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,    alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and    the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,    alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl    substituents can, for their part, in turn be substituted,-    or R7 and R8 are together cycloalkyl or heterocyclyl, where    cycloalkyl and heterocyclyl can, for their part, in turn be    substituted.

R3 and R4 can, independently of each other, be hydrogen or NR9R10 withthe proviso that, when R3=NR9R10, R4=H and when R4=NR9R10, R3=H, whereR9 can be hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, andthe alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroarylsubstituents can, for their part, in turn be substituted, and R10 maybe:

-   -   —C(Y)NR11R12, where Y is O, S and R11 and R12 may be        independently of one another

-   (i) hydrogen,

-   (ii) unsubstituted or substituted alkyl, where the alkyl radical may    have one or more identical or different F, Cl, Br, I, CF₃, CN, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,    NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl,    NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl,    NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl,    NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl,    NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl,    S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃,    O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,    O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,    O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl,    OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl,    OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl,    OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl,    C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,    CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-hetero-cyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl,    SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl,    cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

-   (iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl    radical may have one or more identical or different F, Cl, Br, I,    NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl,    NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl,    NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, OH,    O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,    O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl,    OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl,    OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl,    OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, CO₂H, CO₂-alkyl, CO₂-cycloalkyl,    CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkylcycloalkyl,    CO₂-alkyl-hetero-cyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-aryl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, alkyl or aryl substituents,

-   (iv) unsubstituted or substituted heterocyclyl, where the    heterocyclyl radical may have one or more identical or different OH,    O-alkyl, O-aryl, NH₂, NH-alkyl, NH-aryl, alkyl, alkyl-aryl or aryl    substituents,

-   (v) unsubstituted or substituted aryl, where the aryl radical may    have one or more identical or different F, Cl, Br, I, CF₃, CN, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,    NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl,    NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl,    NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH,    S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH,    OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,    O-alkyl-cycloalkyl, O-alkyl-hetero-cyclyl, O-alkyl-aryl,    O-alkyl-heteroaryl, O-alkyl-OH, O—(CH₂)_(n)—O, OC(O)-alkyl,    OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,    OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl,    OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl,    OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂,    OSO₂-heterocyclyl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl,    OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl,    CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,    CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl,    CO₂-alkyl-heteroaryl, C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl,    C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,    C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl,    C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂,    C(O)N(cycloalkyl)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl,    SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl,    SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl,    SO₂O-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl    substituents, and n may have the value 1, 2 or 3,

-   (vi) unsubstituted or substituted heteroaryl, where the heteroaryl    radical may have one or more identical or different F, Cl, Br, I,    CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl,    NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH,    N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl,    NHC(O)-aryl, NHC(O)-hetero-aryl, NHC(O)-alkyl-aryl,    NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl,    NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl,    NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl, OH,    OCF₃, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl,    O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,    O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl,    OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl,    OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl,    OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl,    C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,    CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl,    SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl,    SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl    substituents,

-   (vii) —C(O)—R17, where R17 may be alkyl, aryl or heteroaryl, and the    alkyl and aryl substituents may in turn themselves be substituted,

-   (viii) or R11 and R12 together may be cycloalkyl or heterocyclyl,    may be —C(Y)NR13R14, where Y is NH and R13 and R14 may be    independently of one another

-   (i) hydrogen,

-   (ii) unsubstituted or substituted alkyl, where the alkyl radical may    have one or more identical or different F, Cl, Br, I, CF₃, CN, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl,    NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl,    NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl,    S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl,    O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl,    O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl,    OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl,    CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl,    CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl,    CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)—NH₂, C(O)NH-alkyl,    C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl,    C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₃H, alkyl, cycloalkyl, heterocyclyl, aryl or    heteroaryl substituents,

-   (iii) unsubstituted or substituted cycloalkyl, where the cycloalkyl    radical may have one or more identical or different F, Cl, Br, I,    NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl,    NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl,    O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl,    OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,    OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, CO₂H,    CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl,    CO₂-heteroaryl, C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl,    C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,    C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, alkyl or    aryl substituents,

-   (iv) unsubstituted or substituted heterocyclyl, where the    heterocyclyl radical may have one or more identical or different OH,    O-alkyl, O-aryl, NH₂, NH-alkyl, NH-aryl, alkyl or aryl substituents,

-   (v) unsubstituted or substituted aryl, where the aryl radical may    have one or more identical or different F, Cl, Br, I, CF₃, CN, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,    NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂,    SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH,    OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,    O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,    O-alkyl-heteroaryl, O-alkyl-OH, O-(CH₂)_(n)—O, OC(O)-alkyl,    OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,    OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl,    C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl,    CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H,    SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl,    heterocyclyl, aryl or heteroaryl substituents, and n may have the    value 1, 2 or 3,

-   (vi) unsubstituted or substituted heteroaryl, where the heteroaryl    radical may have one or more identical or different F, Cl, Br, I,    CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂,    SH, S-alkyl, S-aryl, OH, OCF₃, O-alkyl, O-cycloalkyl,    O-heterocyclyl, O-aryl, O-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl,    OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl,    C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,    CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkylheterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-hetero-cyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂-alkyl, SO₂-aryl, SO₂NH₂,    SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl,    SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or    heteroaryl substituents,

-   (vii) or R13 and R14 together may be cycloalkyl or heterocyclyl, may    be —C(NR15)R16 where R15 is H and R16 may be

-   (i) unsubstituted or substituted alkyl, where the alkyl radical may    have one or more identical or different F, Cl, Br, I, CF₃, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl,    NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl,    NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl,    S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl,    O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl,    O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl,    OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl,    CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl,    CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl,    CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)—NH₂, C(O)NH-alkyl,    C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl,    C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₃H, alkyl, cycloalkyl, heterocyclyl, aryl or    heteroaryl substituents,

-   (ii) unsubstituted or substituted cycloalkyl, where the cycloalkyl    radical may have one or more identical or different F, Cl, Br, I,    NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl,    NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl,    O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl,    OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,    OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, CO₂H,    CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl,    CO₂-heteroaryl, C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl,    C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,    C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, alkyl or    aryl substituents,

-   (iii) unsubstituted or substituted heterocyclyl, where the    heterocyclyl radical may have one or more identical or different OH,    O-alkyl, O-aryl, NH₂, NH-alkyl, NH-aryl, alkyl or aryl substituents,

-   (iv) unsubstituted or substituted aryl, where the aryl radical may    have one or more identical or different F, Cl, Br, I, CF₃, NH₂,    NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,    NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,    NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂,    SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH,    OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,    O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,    O-alkyl-heteroaryl, O-alkyl-OH, O—(CH₂)_(n)—O, OC(O)-alkyl,    OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,    OSO₂-alkyl OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl,    C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl,    CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,    SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H,    SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl,    heterocyclyl, aryl or heteroaryl substituents, and n may have the    value 1, 2 or 3,

-   (v) unsubstituted or substituted heteroaryl, where the heteroaryl    radical may have one or more identical or different F; Cl, Br, I,    CF₃, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,    NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂,    NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,    NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂,    SH, S-alkyl, S-aryl, OH, OCF₃, O-alkyl, O-cycloalkyl,    O-heterocyclyl, O-aryl, O-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,    OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl,    OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl,    C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,    CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,    CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl,    C(O)—NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,    C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl,    C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,    C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,    C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂-alkyl, SO₂-aryl, SO₂NH₂,    SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl,    SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or    heteroaryl substituents;

The term “alkyl” includes for the purpose of this invention acyclicsaturated or unsaturated hydrocarbon radicals which may be branched orstraight-chain and unsubstituted or mono- or polysubstituted, having 1to 8 C atoms, i.e. C₁₋₈-alkanyls, C₂₋₈-alkenyls and C₂₋₈-alkynyls. Inthis connection, alkenyls have at least one C-C double bond and alkynylshave at least one C-C triple bond. Alkyl is preferably selected from thegroup comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-octyl,ethylenyl (vinyl), ethynyl, propenyl (—CH₂CH═CH₂; —CH═CH—CH₃,—C(═CH₂)—CH₃), propynyl (—CH₂—C≡CH, —C≡C—CH₃), butenyl, butynyl,pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl andoctynyl.

The term “cycloalkyl” means for the purposes of this invention cyclichydrocarbon radicals having 3-12 carbon atoms, which may be saturated orunsaturated. It is possible for the linkage to the compounds of thegeneral structure I to take place via any possible ring member of thecycloalkyl radical. The cycloalkyl radical may also be part of a bi- orpolycyclic system.

The term “heterocyclyl” stands for a 3-, 4-, 5-, 6-, 7- or 8-memberedcyclic organic radical which comprises at least 1, where appropriate 2,3, 4 or 5, heteroatoms, the heteroatoms being identical or different andthe cyclic radical being saturated or unsaturated, but not aromatic. Itis possible for the linkage to the compounds of the general structure Ito take place via any possible ring member of the heterocyclyl radical.The heterocycle may also be part of a bi- or polycyclic system.Preferred heteroatoms are nitrogen, oxygen and sulphur. It is preferredfor the heterocyclyl radical to be selected from the group comprisingtetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,piperazinyl and morpholinyl.

The term “aryl” means for the purpose of this invention aromatichydrocarbons having 6 to 14 carbon atoms, inter alia phenyls, naphthylsand anthracenyls. The radicals may also be fused to other saturated,(partially) unsaturated or aromatic ring systems. It is possible for thelinkage to the compounds of the general structure I to take place viaany possible ring member of the aryl radical.

The term “heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromaticradical which comprises at least 1, where appropriate also 2, 3, 4 or 5,heteroatoms, the heteroatoms being identical or different. It ispossible for the linkage to the compounds of the general structure I totake place via any possible ring member of the heteroaryl radical. Theheterocycle may also be part of a bi- or polycyclic system. Preferredheteroatoms are nitrogen, oxygen and sulphur. It is preferred for theheteroaryl radical to be selected from the group comprising pyrrolyl,furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl,indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl,quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.

The terms “alkyl-cycloalkyl”, “alkyl-heterocyclyl”, “alkyl-aryl” or“alkyl-heteroaryl” means for the purposes of the present invention thatalkyl and cycloalkyl, heterocyclyl, aryl and heteroaryl have themeanings defined above, and the cycloalkyl, heterocyclyl, aryl orheteroaryl radical is linked via a C₁₋₈-alkyl group to the compounds ofthe general structure I.

The term substituted in connection with “alkyl”, “cycloalkyl”,“heterocyclyl”, “aryl”, “heteroaryl”, “alkyl-cycloalkyl”,“alkyl-heterocyclyl”, “alkyl-aryl”, and “alkyl-heteroaryl” means for thepurposes of this invention, unless explicitly defined above in thedescription or the claims, replacement of one or more hydrogen radicalsby F, Cl, Br, I, CN, CF₃, NH₂, NH-alkyl, NH-aryl, N(alkyl)₂, NO₂, SH,S-alkyl, OH, OCF₃, O-alkyl, O-aryl, OSO₃H, OP(O)(OH)₂, CHO, CO₂H, SO₃Hor alkyl. The substituents may be identical or different, and thesubstitution may take place at any possible position of the alkyl,cycloalkyl, heterocyclyl, aryl and heteroaryl radical.

Radicals substituted more than once mean those which are substitutedmore than once, e.g. twice or three times, either on different or on thesame atoms, for example three times on the same C atom as in the case ofCF₃, —CH₂CF₃, or in different sites as in the case of—CH(OH)—CH═CH—CHCl₂. Substitution more than once can take place withidentical or different substituents.

Where the compounds of the invention of the general Formula I have atleast one centre of asymmetry, they may exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Anymixing ratio of the stereoisomers in the mixtures is possible.

Thus, for example, the compounds of the invention of the general FormulaI which have one or more centres of chirality and which occur asracemates can be separated by methods known per se into their opticalisomers, i.e. enantiomers or diastereomers. The separation can takeplace by column separation on chiral phases or by recrystallization froman optically active solvent or with use of an optically active acid orbase or through derivatization with an optically active reagent such as,for example, an optically active alcohol, and subsequent elimination ofthe radical.

Where possible, the compounds of the invention may exist in the form oftautomers.

The compounds of the invention of the general Formula I may, if theycontain a sufficiently basic group such as, for example, a primary,secondary or tertiary amine, be converted with inorganic and organicacids into their physiologically tolerated salts. The pharmaceuticallyacceptable salts of the compounds of the invention of the generalstructure I are preferably formed with hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,p-toluenesulphonic acid, carbonic acid, formic acid, acetic acid,trifluoroacetic acid, sulphoacetic acid, oxalic acid, malonic acid,maleic acid, succinic acid, tartaric acid, racemic acid, malic acid,embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid,glutamic acid or aspartic acid. The salts which are formed are, interalia, hydrochlorides, hydrobromides, sulphates, bisulphates, phosphates,methanesulphonates, tosylates, carbonates, bicarbonates, formates,acetates, triflates, sulphoacetates, oxalates, malonates, maleates,succinates, tartrates, malates, embonates, mandelates, fumarates,lactates, citrates, glutamates and aspartates. The stoichiometry of thesalts which are formed of the compounds of the invention may moreover beintegral or nonintegral multiples of one.

The compounds of the invention of the general Formula I may, if theycontain a sufficiently acidic group such as a carboxyl group, beconverted with inorganic and organic bases into their physiologicallytolerated salts. Examples of suitable inorganic bases are sodiumhydroxide, potassium hydroxide, calcium hydroxide, and of organic basesare ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dibenzylethylenediamine and lysine. The stoichiometry of the salts whichare formed of the compounds of the invention may moreover be integral ornonintegral multiples of one.

Preference is likewise given to solvates and, in particular, hydrates ofthe compounds of the invention which can be obtained for example bycrystallization from a solvent or from aqueous solution. It is possiblein these cases for one, two, three or any number of solvate or watermolecules to combine with the compounds of the invention to givesolvates and hydrates.

It is known that chemical substances form solids in various order stateswhich are referred to as polymorphic forms or modifications. The variousmodifications of a polymorphic substance may vary widely in theirphysical properties. The compounds of the invention of the generalFormula I can exist in various polymorphic forms, and certainmodifications may be metastable.

The processes for preparing substituted pyrido[2,3-b]pyrazines of theinvention are explained below.

The compounds of the general Formula I can be obtained as shown in thefollowing schemes (scheme 1-5):

Precursors for selected examples of the pyrido[2,3-b]pyrazines accordingto the invention according to the general Formula I, in which thesubstituents R1 and/or R2 are to be the radicals OR5, SR6, NR7R8, areobtainable for example according to the process in scheme 2 or acorresponding process known to the person skilled in the art.

Precursors for selected examples of the pyrido[2,3-b]pyrazines accordingto the invention according to the general Formula I, in which thesubstituent R9 is not to be equal to H, are obtainable for exampleaccording to the process in scheme 3.

The reaction of the precursors 4, 7, and 13 from schemes 1-3 to give thesubstituted pyrido[2,3-b]pyrazines according to the invention accordingto the general Formula I can be effected for example according to theprocesses in scheme 4.

Selected examples of the pyrido[2,3-b]pyrazines according to theinvention according to the general formula I, in which the substituentsR1 and R2 may be selected carboxylic ester-, carboxamide-, sulphonicester- or sulphonamide-substituted radicals are obtainable for exampleaccording to the process in scheme 5 or corresponding processes known tothe person skilled in the art.

R17=alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-aryl,alkyl-heteroaryl

The starting compounds are either commercially available or can beprepared by procedures known per se. Precursors 4, 7 and 10-13 arevaluable intermediates for the preparation of the pyridopyrazines of theinvention of the general Formula I.

For the preparation of the starting compounds and target compounds,reference may be made for example to the following primary literature,the contents of which are herein incorporated by reference in theirentirety.

1) Houben-Weyl, Methoden der Organischen Chemie, volume 4/1a, pp.343-350

2) Houben-Weyl, Methoden der Organischen Chemie, 4th edition, volume E7b (part 2), p. 579; Degussa GB 1184848 (1970); S. Seko, et al. EP735025 (1996)

3) D. Catarzi, et al.; J. Med. Chem. 1996, 1330-1336; J. K. Seydel, etal.; J. Med. Chem. 1994, 3016-3022

4) Houben-Weyl, Methods of Organic Chemistry, volume E 9c, pp. 231-235

5) Houben-Weyl/Science of Synthesis, Volume 16, p. 1269

6) C. Goenczi, et al. J. Chem. Soc. Perkin Trans. 1 2000, 9, 1417-1422

7) M. S. A. El-Gaby, et al. Indian J. Chem. Sect. B 2001, 40, 195-200;M. R. Myers, et al. Bioorg. Med. Chem. Lett. 2003, 13, 3091-3096; A. R.Renslo, et al. J. Amer. Chem. Soc. 1999, 121, 7459-7460; C. O. Okafor,et al. J. Heterocyclic Chemistry 1983, 20, 199-203

8) J. Yin, et al. Org. Lett. 2002, 4, 3481-3484; O. A. El-Sayed, et al.Arch. Pharm. 2002, 335, 403-410; C. Temple, et al. J. Med. Chem. 1992,35, 988-993

9) A. M. Thompson, et al. J. Med. Chem. 2000, 4200-4211

10) G. Heinisch, et al. Arch. Pharm. 1997, 207-210

11) N. A. Dales, et al. Org. Lett. 2001, 2313-2316; G. Dannhardt, et al.Arch. Pharm. 2000, 267-274

12) M. L. Mussous, et al. Tetrahedron 1999, 4077-4094; A. Kling, et al.Bioorg. Med. Chem. Lett. 2002, 441-446

13) I. K. Khanna, et al. J. Med. Chem. 2000,3168-3185

14) L. Younghee, et al. Bioorg. Med. Chem. Lett. 2000, 2771-2774; N. L.Reddy et al. J. Med. Chem. 1998, 3298-3302

15) A. V. Wizuycia, et al. J. Org. Chem. 2002, 67, 7151-7154; K. Kano,et al. J. Amer. Chem. Soc. 2002, 124, 9937-9944; M. L. Bushey, et al. J.Amer. Chem. Soc. 2003, 125, 8264-8269, A. Casini, et al. Bioorg. Med.Chem. Lett. 2003, 13, 837-840.

General Method for the Preparation of the Compounds of the GeneralFormula I:

Scheme 1: 1st Stage

2,6-Diamino-3-nitropyridine or 2-amino-3,5-dinitropyridine are dissolvedin a suitable, inert solvent such as, for example, methanol, ethanol,dimethylformamide or dioxane. After addition of a catalyst, for exampleRaney nickel, palladium on carbon or platinum(IV) dioxide, the reactionmixture is put under a hydrogen atmosphere, adjusting a pressure between1 and 5 bar. The reaction mixture is left to react in a temperaturerange between 20° C. and 60° C. for several hours, for example 1-16hours. After the reaction is complete, the insoluble residues arefiltered off, it being possible for the filter medium to consist forexample of silica gel, Celite or commercially available glass fibrefilters, and washed with the appropriate solvent. The crude product isused in solution, without further purification, for the next reaction.

2nd Stage

The 1,2-dione derivative is introduced into a suitable, inert solvent,for example methanol, ethanol, dioxane, toluene or dimethylformamide.2,3,6-Triaminopyridine or 2,3,5-triaminopyridine are added immediatelyafter the reduction as a solution of the crude products in one of theabovementioned solvents to the introduced 1,2-dione, where appropriatewith addition of an acid such as, for example, acetic acid, or of abase, for example potassium hydroxide. The reaction mixture is left toreact in a temperature range from 20° C. to 80° C. for some time, forexample 20 minutes to 40 hours. After the reaction is complete, anyprecipitate which has separated out is filtered off, it being possiblefor the filter medium to consist for example of commercially availablefilter paper, and washed with the appropriate solvent, and the remainingsolid is dried in vacuo, or the reaction mixture is freed of solvent invacuo. On use of dimethylformamide, the reaction mixture is stirred intoa large amount of water, and the precipitate which has separated out isfiltered off, or the aqueous phase is extracted with a suitable organicsolvent, such as, e.g. dichloromethane or ethyl acetate, and the organicphases are concentrated in vacuo. The remaining crude product ispurified by recrystallization from a suitable solvent, for exampledioxane, or by column or flash chromatography on silica gel or alumina.A mixture of methanol and dichloromethane is used for example as mobilephase.

Scheme 2: 1st Stage

2,3,6-Triaminopyridine or 2,3,5-triaminopyridine are introduced,directly after the reduction, as a solution of the crude products in oneof the abovementioned solvents. After an oxalic acid derivative, such asdiethyl oxalate or oxalyl chloride, has been added, the reaction mixtureis left to react, where appropriate in the added presence of an acid,such as hydrochloric acid, sulphuric acid or glacial acetic acid, in atemperature range of from 20° C. to 150° C. for some time, for examplefrom 10 minutes to 24 hours. After the reaction is complete, aprecipitate which has separated out is filtered off, it being possiblefor the filter medium to consist for example of commercially availablefilter paper, and washed with the appropriate solvent, and the remainingsolid is dried in vacuo, or the reaction mixture is freed of solvent invacuo. On use of dimethylformamide, the reaction mixture is stirred intoa large quantity of water and the precipitate which has separated out isfiltered off or the aqueous phase is extracted with a suitable organicsolvent, such as dichloromethane or ethylacetate, and the organic phasesare concentrated in vacuo. The remaining crude product is purified byrecrystallization from a suitable solvent, for example dioxane ortoluene, or by column or flash chromatography on silica gel or alumina.A mixture of methanol and dichloromethane is used, for example, as themobile phase.

2nd Stage

The dione derivative 8 is introduced in a suitable, inert solvent, forexample dimethylformamide, dioxane or toluene, or without any solvent. Achlorinating agent, for example phosphoryl chloride or thionyl chloride,is added at room temperature and the reaction mixture is left to reactin a temperature range of from 20° C. to 100° C. for some time, forexample from 1 hour to 24 hours. After the reaction is complete, thereaction mixture is poured onto water and neutralized with a suitableaqueous base, for example sodium hydroxide solution. Any precipitatewhich has separated out is filtered off, it being possible for thefilter medium to consist for example of commercially available filterpaper, and washed with the corresponding solvent, and the remainingsolid is dried in vacuo, or the aqueous phase is extracted with asuitable organic solvent, for example dichloromethane or ethyl acetate,and the organic phases are concentrated in vacuo. The remaining crudeproduct is purified by recrystallization from a suitable solvent, forexample dioxane or toluene, or by column or flash chromatography onsilica gel or alumina. A mixture of methanol and dichloromethane isused, for example, as the mobile phase.

3rd Stage

The intermediate 9 can be reacted with an appropriate alcohol, thiol oramine and, where appropriate, with a suitable base, preferably sodiumhydride, pyridine, triethylamine, potassium carbonate or sodiummethoxide in methanol, in a suitable, inert solvent, such asdimethylformamide, dimethyl sulphoxide, methanol or toluene, or in abase as solvent, such as pyridine or triethylamine, or without anysolvent. The reaction mixture is left to react for some time, forexample for from 30 minutes to 2 days, in a temperature range between20° C. and 140° C. After the reaction is complete, any precipitate whichhas separated out is filtered off, it being possible for the filtermedium to consist for example of commercially available filter paper,and washed with the appropriate solvent, and the remaining solid isdried in vacuo, or the reaction mixture is freed from the solvent invacuo. When using dimethylformamide or dimethyl sulphoxide, the reactionmixture is stirred into a large quantity of water and the precipitatewhich has separated out is filtered off or the aqueous phase isextracted with a suitable organic solvent, such as dichloromethane orethyl acetate, and the organic phases are concentrated in vacuo. Theremaining crude product is purified by recrystallization from a suitablesolvent, for example dioxane or toluene, or by column or flashchromatography on silica gel or alumina. A mixture of methanol anddichloromethane is used, for example, as the mobile phase.

Scheme 3: 1st Stage

The intermediates 4 and 7 can be reacted with an appropriate, suitablechloride, bromide or tosylate and, where appropriate, with a suitablebase, preferably sodium hydride, pyridine, triethylamine, potassiumcarbonate or sodium methoxide in methanol, in a suitable, inert solvent,such as dimethylformamide, dimethyl sulphoxide or methanol, or in abase, as solvent, such as pyridine or triethylamine, or without anysolvent. The reaction mixture is left to react for some time, forexample for from 1 hour to 24 hours, in a temperature range between 20°C. and 150° C. Alternatively, the intermediates 4 and 7 can be reactedwith an appropriate aryl bromide or aryl iodide and a suitable catalyst,such as palladium acetate or Pd₂(dba)₃, and a suitable ligand, such asBINAP, and a suitable base, for example potassium carbonate or sodiumtert-butoxide, in a suitable solvent, such as toluene or dioxane. Thereaction mixture is left to react for some time, for example for from 10hours to 30 hours, in a temperature range between 60° C. and 120° C.After the reaction is complete, any precipitate which has separated outis filtered off, it being possible for the filter medium to consist forexample of commercially available filter paper, and washed with theappropriate solvent, and the remaining solid is dried in vacuo, or anycatalyst residues which may be present are filtered off and washed withthe appropriate solvent, and the solvent is removed in vacuo, or thereaction mixture is freed from the solvent in vacuo. Whendimethylformamide or dimethyl sulphoxide is used, the reaction mixtureis stirred into a large quantity of water and the precipitate which hasseparated out is filtered off, or the aqueous phase is extracted with asuitable organic solvent, such as dichloromethane or ethyl acetate, andthe organic phases are concentrated in vacuo. The remaining crudeproduct is purified by recrystallization from a suitable solvent, forexample EtOH, or by column or flash chromatography on silica gel oralumina. A mixture of methanol and dichloromethane is used, for example,as the mobile phase.

Scheme 4: 1st Stage

Following the basic processes it is possible to convert in subsequentreactions the products resulting from the basic process into subsequentproducts of the invention of the Formula I in a procedure known to theskilled person.

Thus, if the product is to be a derivative of the compound 14 as shownin scheme 4, the reaction product 4, 7 or 13 after completion of thebasic reactions can be reacted with an appropriate isocyanate and, whereappropriate, a suitable base, preferably sodium hydride, potassiumhexamethyldisilazide, pyridine, triethylamine or potassium carbonate, ina suitable inert solvent such as, for example, dimethylformamide,dimethyl sulphoxide, acetonitrile, dichloromethane, 1,2-dichloroethaneor dioxane, or in a base as solvent, such as, e.g., pyridine ortriethylamine, or without solvent. The reaction mixture is left to reactin a temperature range between 0 and 80° C. for several hours, forexample 1-24 hours. After the reaction is complete, any precipitatewhich has separated out is filtered off, it being possible for thefilter medium to consist for example of commercially available filterpaper, and washed with the appropriate solvent, and the remaining solidis dried in vacuo, or the reaction mixture is freed of solvent in vacuo.On use of dimethylformamide or dimethyl sulphoxide, the reaction mixtureis stirred into a large amount of water, and the precipitate which hasseparated out is filtered off, or the aqueous phase is extracted with asuitable organic solvent, such as, e.g., dichloromethane or ethylacetate and the organic phases are concentrated in vacuo. The remainingcrude product is purified by recrystallization from a suitable solvent,for example ethanol or ethyl acetate, or by column or flashchromatography on silica gel or alumina. A mixture of methanol anddichloromethane is used for example as mobile phase.

An alternative possibility if the product is to be a derivative of thecompound 15 shown in scheme 4 is, after completion of the basicreactions, to react the reaction product 4, 7 or 13 with phosgene orcarbonyldiimidazole and an appropriate amine in a suitable inert solventsuch as, for example, dimethylformamide, tetrahydrofuran, toluene,dichloromethane or acetonitrile. A suitable base is used whereappropriate, preferably pyridine, sodium bicarbonate, triethylamine,N-methylmorpholine or sodium acetate. The reaction mixture is left toreact in a temperature range between 0 and 60° C. for some time, forexample 15 minutes to 24 hours. After the reaction is complete, anyprecipitate which has separated out is filtered off, it being possiblefor the filter medium to consist for example of commercially availablefilter paper, and washed with the appropriate solvent, and the remainingsolid is dried in vacuo, or the reaction mixture is freed of solvent invacuo. On use of dimethylformamide, the reaction mixture is stirred intoa large amount of water, and the precipitate which has separated out isfiltered off, or the aqueous phase is extracted with a suitable organicsolvent such as, e.g., dichloromethane or ethyl acetate and the organicphases are concentrated in vacuo. The remaining crude product ispurified by recrystallization from a suitable solvent, for exampleethanol or ethyl acetate, or by column or flash chromatography on silicagel or alumina. A mixture of methanol and dichloromethane is used forexample as mobile phase.

Thus, if the product is to be a derivative of the compound 16 shown inscheme 4, the reaction product 4, 7 or 13 after completion of the basicreactions can be reacted with an appropriate isothiocyanate and, whereappropriate, a suitable base, preferably sodium hydride, triethylamine,potassium carbonate or pyridine, in a suitable inert solvent such as,for example, dimethylformamide, tetrahydrofuran, acetone or toluene, orin a base as solvent, such as, e.g., pyridine or triethylamine, orwithout solvent. The reaction mixture is left to react in a temperaturerange between 0 and 115° C. for some time, for example 30 minutes to 90hours. After the reaction is complete, any precipitate which hasseparated out is filtered off, it being possible for the filter mediumto consist for example of commercially available filter paper, andwashed with the appropriate solvent, and the remaining solid is dried invacuo, or the reaction mixture is freed of solvent in vacuo. On use ofdimethylformamide, the reaction mixture is stirred into a large amountof water, and the precipitate which has separated out is filtered off,or the aqueous phase is extracted with a suitable organic solvent suchas, e.g. dichloromethane or ethyl acetate and the organic phases areconcentrated in vacuo. The remaining crude product is purified byrecrystallization from a suitable solvent, for example ethanol or ethylacetate, or by column or flash chromatography on silica gel or alumina.A mixture of methanol and dichloromethane is used for example as mobilephase.

An alternative possibility if the product is to be a derivative of thecompound 17 shown in scheme 4 is, after completion of the basicreactions, to react the reaction product 4, 7 or 13 with thiophosgene orthiocarbonyldiimidazole and an appropriate amine in a suitable inertsolvent such as, for example, dimethylformamide, tetrahydrofuran,toluene, dichloromethane, ethanol or acetonitrile. A suitable base isused where appropriate, preferably pyridine, sodium bicarbonate,potassium carbonate, triethylamine or imidazole. The reaction mixture isleft to react in a temperature range between −10 and 80° C. for severalhours, for example 1 to 24 hours. After the reaction is complete, anyprecipitate which has separated out is filtered off, it being possiblefor the filter medium to consist for example of commercially availablefilter paper, and washed with the appropriate solvent, and the remainingsolid is dried in vacuo, or the reaction mixture is freed of solvent invacuo. On use of dimethylformamide, the reaction mixture is stirred intoa large amount of water, and the precipitate which has separated out isfiltered off, or the aqueous phase is extracted with a suitable organicsolvent such as, e.g., dichloromethane or ethyl acetate and the organicphases are concentrated in vacuo. The remaining crude product ispurified by recrystallization from a suitable solvent, for exampleethanol or ethyl acetate, or by column or flash chromatography on silicagel or alumina. A mixture of methanol and dichloromethane is used forexample as mobile phase.

Thus, if the product is to be a derivative of compound 18 shown inscheme 4, the reaction product 4, 7 or 13 after completion of the basicreactions can be reacted with an appropriate amino nitrile and, whereappropriate, a suitable base, preferably triethylamine or pyridine, or asuitable acid, preferably hydrochloric acid, in a suitable inert solventsuch as, for example, acetone, toluene, chlorobenzene, ethanol,tetrahydrofuran or dimethyl sulphoxide, or in a base as solvent, suchas, e.g., pyridine or triethylamine, or without solvent. The reactionmixture is left to react in a temperature range between 20 and 135° C.for several hours, for example 2 to 140 hours. After the reaction iscomplete, any precipitate which has separated out is filtered off, itbeing possible for the filter medium to consist for example ofcommercially available filter paper, and washed with the appropriatesolvent, and the remaining solid is dried in vacuo, or the reactionmixture is freed of solvent in vacuo. The remaining crude product ispurified by recrystallization from a suitable solvent, for exampledioxane, or by column or flash chromatography on silica gel or aluminaor by HPLC. A mixture of methanol and dichloromethane for example isused as mobile phase, or in the case of HPLC purification a mobile phasemixture of acetonitrile and water for example.

Alternatively, if the product is to be a derivative of compound 19 shownin scheme 4, the reaction product 4, 7 or 13 after completion of thebasic reactions can be reacted with an appropriate nitrile and, whereappropriate, a suitable base, preferably sodium hydride, pyridine,triethylamine or sodium hexamethyldisil-azide, or a suitable catalyst,for example aluminium trichloride, trimethylaluminium, glacial aceticacid or sulphuric acid, in a suitable inert solvent such as, forexample, dioxane, toluene or ethanol, or in a base as solvent, such as,e.g., pyridine or triethylamine, or without solvent. The reactionmixture is left to react in a temperature range between 0 and 200° C.for some time, for example 30 minutes to 24 hours. After the reaction iscomplete, any precipitate which has separated out is filtered off, itbeing possible for the filter medium to consist for example ofcommercially available filter paper, and washed with the appropriatesolvent, and the remaining solid is dried in vacuo, or the reactionmixture is freed of solvent in vacuo. The remaining crude product ispurified by recrystallization from a suitable solvent, for exampledioxane, or by column or flash chromatography on silica gel or aluminaor by HPLC. A mixture of methanol and dichloromethane for example isused as mobile phase or in the case of HPLC purification a mobile phasemixture of acetonitrile and water for example.

Scheme 5: 1st Stage

Following the basic processes it is possible to convert in subsequentreactions the products resulting from the basic process into subsequentproducts of the invention of the Formula I in a procedure known to theskilled person.

Thus, if the product is to be a derivative of the compound 21 or 24 asshown in scheme 5, the reaction product 20 or 23 after completion of thebasic reactions can be reacted with an appropriate carbonyl chlorideand, where appropriate, a suitable base, preferably sodium hydride,potassium hydroxide, pyridine, triethylamine or potassium carbonate, ina suitable inert solvent such as, for example, tetrahydrofuran, toluene,acetonitrile, dichloromethane, acetone or dioxane, or in a base assolvent, such as, e.g. pyridine or triethylamine, or without solvent.The reaction mixture is left to react in a temperature range between 0and 110° C. for some time, for example 30 minutes to 12 hours. After thereaction is complete, any precipitate which has separated out isfiltered off, it being possible for the filter medium to consist forexample of commercially available filter paper, and washed with theappropriate solvent, and the remaining solid is dried in vacuo, or thereaction mixture is freed of solvent in vacuo. Alternatively, thereaction mixture can be stirred into a large amount of water, and theprecipitate which has separated out filtered off; or the aqueous phase,after neutralization with a suitable aqueous acid, such as, e.g.,hydrochloric acid, can be extracted with a suitable organic solvent,such as, e.g. dichloromethane or ethyl acetate and the organic phase canbe concentrated in vacuo. The remaining crude product is purified byrecrystallization from a suitable solvent, for example ethanol, or bycolumn or flash chromatography on silica gel or alumina. A mixture ofmethanol and dichloromethane is used for example as mobile phase.

An alternative possibility if the product is to be a derivative of thecompound 22 or 25 shown in scheme 5 is, after completion of the basicreactions, to react the reaction product 20 or 23 with an appropriatesulphonyl chloride and, where appropriate, a suitable base, preferablysodium hydride, potassium hydroxide, pyridine, triethylamine orpotassium carbonate, in a suitable inert solvent such as, for example,tetrahydrofuran, toluene, acetonitrile, dichloromethane, acetone,dimethylformamide or dioxane, or in a base as solvent, such as, e.g.pyridine or triethylamine, or without solvent. The reaction mixture isleft to react in a temperature range between 0 and 80° C. for some time,for example 30 minutes to 16 hours. After the reaction is complete, anyprecipitate which has separated out is filtered off, it being possiblefor the filter medium to consist for example of commercially availablefilter paper, and washed with the appropriate solvent, and the remainingsolid is dried in vacuo, or the reaction mixture is freed of solvent invacuo. Alternatively, the reaction mixture can be stirred into a largeamount of water, and the precipitate which has separated out can befiltered off, or the aqueous phase, after neutralization with a suitableaqueous acid, such as, e.g., hydrochloric acid, can be extracted with asuitable organic solvent, such as, e.g. dichloromethane or ethyl acetateand the organic phase can be concentrated in vacuo.

On use of dimethylformamide, the reaction mixture is stirred into alarge amount of water, and the precipitate which has separated out isfiltered off, or the aqueous phase is extracted with a suitable organicsolvent, such as, e.g., dichloromethane or ethyl acetate and the organicphases are concentrated in vacuo. The remaining crude product ispurified by recrystallization from a suitable solvent, for exampleethanol, or by column or flash chromatography on silica gel or alumina.A mixture of methanol and dichloromethane is used for example as mobilephase.

Under some of the reaction conditions mentioned, OH, SH and NH₂ groupsmay possibly undergo unwanted side reactions. It is therefore preferredfor them to be provided with protective groups, or be replaced by NO₂ inthe case of NH₂, for the protective group subsequently to be eliminatedor the NO₂ group to be reduced.

Thus, in a modification of the processes described above, at least oneOH group in the starting compounds can be replaced for example by abenzyloxy group and/or at least one SH group can be replaced for exampleby an S-benzyl group and/or at least one NH₂ group can be replaced by anNO₂ group. It is subsequently possible to eliminate at leastone—preferably all—benzyloxy group(s) for example with hydrogen andpalladium on carbon and/or at least one—preferably all—S-benzyl group(s)for example with sodium in ammonia and/or to reduce at leastone—preferably all—NO₂ group(s) for example with hydrogen and Raneynickel to NH₂.

Under some of the reaction conditions mentioned, OH, NH₂ and COOH groupsmay possibly undergo unwanted side reactions. It is therefore preferredto convert starting compounds and intermediates which contain at leastone OH and/or at least one NH₂ and/or at least one COOH group into thecorresponding carboxylic ester and carboxamide derivatives. In amodification of the processes described above, starting compounds andintermediates having at least one OH group and/or having at least oneNH₂ group can be converted by reaction with an activated carboxyl group,for example a carbonyl chloride group, into carboxylic ester orcarboxamide derivatives. In a modification of the processes describedabove, starting compounds and intermediates having at least one COOHgroup can be converted by reaction with an activator such as, forexample, thionyl chloride or carbonyldiimidazole and subsequent reactionwith a suitable alcohol or amine into carboxylic ester or carboxamidederivatives.

The pyrido[2,3-b]pyrazine derivatives of the invention of the generalFormula I are suitable as active ingredients in medicaments for themodulation of misdirected cellular signal transduction processes, inparticular for influencing the function of tyrosine and serine/threoninekinases and in the case of malignant or benign oncoses, such as, e.g. ofthe breast, prostate, lung, skin and ovaries and other disorders basedon pathological cell proliferations, such as, for example, restenosis,psoriasis, arteriosclerosis and cirrhosis of the liver for the treatmentof humans, mammals and poultry. Mammals may be domestic animals such ashorses, cows, dogs, cats, rabbits, sheep and the like.

The medicinal effect of the pyrido[2,3-b]pyrazine derivatives of theinvention may be based for example on modulation of signal transductionthrough interaction with receptor tyrosine kinases and with cytoplasmictyrosine and serine/threonine kinases. In addition, other known andunknown mechanisms of action for controlling malignant processes arealso conceivable.

A further aspect of the invention provides a method for controllingtumours in humans, in mammals and in poultry, which is characterized inthat at least one pyrido[2,3-b]pyrazine derivative of the generalFormula I is administered to a human, a mammal or poultry in an amounteffective for tumour treatment. The therapeutically effective dose ofthe particular pyrido[2,3-b]pyrazine derivative of the invention to beadministered for the treatment depends inter alia on the nature andstage of the oncosis, the age and sex of the patient, the mode ofadministration and the duration of treatment. The medicaments of theinvention may be administered as liquid, semisolid and solidpharmaceutical forms. This takes place in the manner suitable in eachcase in the form of aerosols, powders, dusting powders and epipastics,tablets, coated tablets, emulsions, foams, solutions, suspensions, gels,ointments, pastes, pills, pastilles, capsules or suppositories.

The pharmaceutical forms comprise besides at least one ingredient of theinvention, depending on the pharmaceutical form employed, whereappropriate auxiliary substances such as, inter alia, solvents, solutionpromoters, solubilizers, emulsifiers, wetting agents, antifoams, gellingagents, thickeners, film formers, binders, buffers, salt formers,desiccants, flow regulators, fillers, preservatives, antioxidants,colours, mould release agents, lubricants, disintegrants, and maskingtastes and odours. The selection of the auxiliary substances, and theamounts thereof to be employed, depends on the chosen pharmaceuticalform and is based on the formulas known to the skilled person.

The medicaments of the invention can be administered in a suitabledosage form to the skin, epicutaneously as solution, suspension,emulsion, foam, ointment, paste or plaster; via the oral and lingualmucosa, buccally, lingually or sublingually as tablet, pastille, coatedtablet, linctus or gargle; via the gastric and intestinal mucosa,enterally as tablet, coated tablet, capsule, solution, suspension oremulsion; via the rectal mucosa, rectally as suppository, rectal capsuleor ointment; via the nasal mucosa, nasally as drops, ointments or spray;via the bronchial and alveolar epithelium, by the pulmonary route or byinhalation as aerosol or inhalant; via the conjunctiva, conjunctivallyas eye drops, eye ointment, eye tablets, lamellae or eye lotion; via themucosa of the genital organs, intravaginally as vaginal suppositories,ointments and douche, by the intrauterine route as uterine pessary; viathe urinary tract, intraurethrally as irrigation, ointment or bougie;into an artery, arterially as injection; into a vein, intravenously asinjection or infusion; into the skin, intracutaneously as injection orimplant; under the skin, subcutaneously as injection or implant; intothe muscle, intramuscularly as injection or implant; into the abdominalcavity, intraperitoneally as injection or infusion.

The medicinal effect of the compounds of the invention of the generalstructure I can be prolonged by suitable measures in the light ofpractical therapeutic requirements. This aim can be achieved by chemicaland/or pharmaceutical means. Examples of the achievement of aprolongation of the effect are the use of implants and liposomes, theformation of salts and complexes of low solubility, or the use ofcrystal suspensions.

Particularly preferred medicaments in this connection are those whichcomprise at least one compound from the following group ofpyrido[2,3-b]pyrazine derivatives of the general structure I and whichmay be in the form of their free base or else as pharmaceuticallyacceptable salts of physiologically tolerated acids:

1-allyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 1)

1-allyl-3-(3-naphthalen-2-ylpyrido[2,3-b]pytazin-6-yl)thiourea (Example2)

1-allyl-3-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea(Example 3)

1-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thioureahydrochloride (Example 4)

1-(2-methylallyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example5)

1-(2-methylallyl)-3-(3-naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)thiourea(Example 6)

1-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl)-3-(2-methylallyl)thiourea(Example 7)

1-(3-naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)-3-(4-nitrophenyl)thiourea(Example 8)

1-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitrophenyl)thiourea(Example 9)

1-tert-butyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 10)

1-cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 11)

1-methyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 12)

1-benzyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 13)

1-(4-fluorophenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea(Example 14)

1-cyclohexyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 15)

1-isopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea (Example 16)

1-furan-2-ylmethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea(Example 17)

1-methyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea (Example18)

1-[3-(4-hydroxyphenyl)pyrido[2,3-]pyrazin-6-yl]-3-methylthiourea(Example 19)

1-allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea (Example20) ethyl 4-[6-(3-allylthiourea)pyrido[2,3-b]pyrazin-3-yl]benzoate(Example 21)

1-allyl-3-[3-(3-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea(Example 22)

1-allyl-3-(3-benzo[1,3]dioxol-5-ylpyrido[2,3-b]pyrazin-6-yl)thiourea(Example 23)

1-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-prop-2-ynylthiourea(Example 24)

1-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea(Example 25)

1-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(propenyl)thiourea(Example 26)

1-allyl-3-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea(Example 27)

1-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(propenyl)thiourea(Example 28)

1-allyl-3-[2-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea(Example 29)

1-allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-7-yl]thiourea (Example30)

1-cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea (Example 31)

1-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]urea (Example32)

1-(3-phenylpyrido[2,3-b]pyrazin-6-yl)-3-p-tolylurea (Example 33)

1-(4-chloro-3-trifluoromethylphenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea(Example 34)

1-(2-morpholin-4-ylethyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea(Example 35)

1-phenethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea (Example 36)

1-(2,3-dipyridin-2-ylpyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (Example 37)

1-(2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (Example 38)

Exemplary Embodiments

The following compounds, which are evident from the statement of therespective chemical name from the survey hereinafter, were synthesizedin accordance with the general synthesis methods on which the synthesisschemes 1-4 are based. In addition, their NMR spectroscopic data andmelting points are appended. The structure of these compounds areevident from the general Formula II and the substituents R1, R2, R3, R4,and R5 and Y in Table 1 which follows.

The chemicals and solvents employed were obtained commercially fromconventional suppliers (Acros, Aldrich, Fluka, Lancaster, Maybridge,Merck, Sigma, TCI, etc.) or synthesized.

The invention is to be explained in more detail by means of thefollowing examples without being restricted thereto.

EXAMPLE 1 Preparation of 3-phenylpyrido[2,3-b]pyrazin-6-ylamine(reaction shown in scheme 1, 1st and 2nd stage)

A solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210ml of ethanol is hydrogenated with Raney nickel as catalyst at 50° C.and 5 bar. After the hydrogenation is complete, the catalyst is filteredoff with suction through a glass fibre filter. Before the filtration,1.68 g of phenylglyoxal hydrate (11.03 mmol) are introduced into 50 mlof ethanol in the receiver. The catalyst is then filtered off undernitrogen as protective gas, and the hydrogenation solution is suckeddirectly into the reaction flask. The greenish blue reaction mixture isheated under reflux under nitrogen for 30 min. The mixture is allowed tocool, and the solvent is removed in vacuo. A dark brown solid is finallyobtained. Purification by column chromatography on silica gel (mobilephase dichloromethane/methanol mixture) affords a pale yellowcrystalline solid.

Preparation of 1-allyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea(reaction shown in scheme 4, 1st stage)

0.246 g of sodium hydride (6.14 mmol) is introduced into 5 ml ofanhydrous dimethylformamide under nitrogen as protective gas. Themixture is cooled to 0° C. in an ice bath. 1.05 g of3-phenylpyrido[2,3-b]pyrazin-6-ylamine (4.72 mmol) are dissolved in 5 mlof anhydrous dimethylformamide and added dropwise. The cooling bath isremoved, and the mixture is left to stir at RT for 30 minutes. Themixture is then cooled to 0° C. again in the ice bath, and 0.469 g ofallyl isothiocyanate (4.72 mmol), dissolved in 4 ml of anhydrousdimethylformamide, is added dropwise. After the addition is complete,the cooling bath is removed, and the mixture is then left to stir atroom temperature for 1.5 hours. For working up, the mixture is pouredinto about 250 ml of distilled water, and the precipitated orange solidis filtered off with suction. Purification by column chromatographyseveral times (mobile phases dichloromethane/methanol mixtures) andsubsequent purification by preparative HPLC afford a yellow solid.

Melting point: 239-240° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=4.40 (m, 2H), 5.30 (d, 1H), 5.60 (d, 1H), 6.07-6.17(m, 1H), 7.55-7.70 (m, 4H), 8.35 (d, 2H), 8.45 (d, 1H), 9.50 (s, 1H),11.35 (s, 1H), 12.55 (m, 1H).

The following examples were synthesized as in Example 1 and the generalsynthesis methods:

EXAMPLE 2 1-Allyl-3-(3-naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 242-243° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=4.42 (m, 2H), 5.37 (d, 1H), 5.65 (d, 1H), 6.07-6.19(m, 1H), 7.57-7.68 (m, 3H), 7.97-8.05 (m, 1H), 8.07-8.19 (m, 2H),8.40-8.52 (m, 2H), 8.99 (s, 1H), 9.70 (s, 1H), 11.36 (s, 1H), 12.56 (t,1H).

EXAMPLE 31-Allyl-3-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 240-241° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=3.87 (s, 3H), 4.36-4.42 (m, 2H), 5.32 (d, 1H), 5.60(d, 1H), 6.06-6.16 (m, 1H), 7.16 (d, 2H), 7.60 (d, 1H), 8.32 (d, 2H),8.42 (d, 1H), 9.56 (s, 1H), 11.29 (s, 1H), 12.56 (m, 1H).

EXAMPLE 41-Allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thioureahydrochloride

m.p.: 160-161° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=4.36-4.43 (m, 2H), 5.31 (d, 1H), 5.59 (d, 1H),6.05-6.16 (m, 1H), 6.97 (d, 2H), 7.57 (d, 1H), 8.20 (d, 2H), 8.40 (d,1H), 9.41 (s, 1H), 10.17 (bs, 1H), 11.24 (s, 1H), 12.56 (m, 1H).

EXAMPLE 51-(2-Methylallyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 225-226° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=1.90 (s, 3H), 4.30-4.35 (m, 2H), 5.01 (s, 1H), 5.22(s, 1H), 7.55-7.80 (m, 4H), 8.30-8.38 (m, 2H), 8.45 (d, 1H), 9.52 (s,1H), 11.32 (s, 1H), 12.65 (m, 1H).

EXAMPLE 61-(2-Methylallyl)-3-(3-naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 239-240° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=1.94 (s, 3H), 4.32 (m, 2H), 5.07 (s, 1H), 5.28 (s,1H), 7.60-7.69 (m, 3H), 8.00-8.5 (m, 1H), 8.07-8.12 (m, 1H), 8.14 (d,1H), 8.42-8.51 (m, 2H), 8.98 (s, 1H), 9.68 (s, 1H), 11.32 (s, 1H), 12.78(m, 1H).

EXAMPLE 71-[3-(4-Methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(2-methylallyl)thiourea

m.p.: 251-252° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=1.92 (s, 3H), 3.85 (s, 3H), 4.27-4.35 (m, 2H), 5.02(s, 1H), 5.24 (s, 1H), 7.15 (d, 2H), 7.58 (d, 1H), 8.31 (d, 2H), 8.41(d, 1H), 9.46 (s, 1H), 11.29 (s, 1H), 12.68 (m, 1H).

EXAMPLE 81-(3-Naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)-3-(4-nitrophenyl)thiourea

m.p.: 260-261° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=7.61-7.68 (m, 3H), 7.72 (d, 2H), 7.75 (d, 1H),8.01-8.01-8.06 (m, 1H), 8.16 (m, 2H), 8.26 (d, 2H), 8.53 (d, 1H), 8.58(d, 1H), 9.04 (s, 1H), 9.62 (s, 1H), 9.76 (s, 1H), 11.81 (s, 1H).

EXAMPLE 91-[3-(4-Methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitrophenyl)thiourea

m.p.: 250-251° C. (decomp.)

¹H-NMR (d₆-DMSO): δ 3.85 (s, 3H), 7.17 (d, 2H), 7.71 (d, 2H), 8.21 (d,2H), 8.22-8.27 (m, 1H), 8.36-8.42 (m, 3H), 9.53 (s, 1H), 9.65 (s, 1H),11.77 (s, 1H).

EXAMPLE 10 1-tert-Butyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 227° C. (decomp.)

¹H-NMR (d₆-DMSO): δ=1.65 (s, 9H), 7.53-7.69 (m, 4H), 8.34 (d, 2H), 8.41(d, 1H), 9.51 (s, 1H), 10.98 (s, 1H), 12.75 (s, 1H).

EXAMPLE 11 1-Cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 233-234° C.

¹H-NMR (d₆-DMSO): δ=0.70-0.80 (m, 2H), 0.91-1.00 (m, 2H), 3.20-3.28 (m,1H), 7.51-7.72 (m, 4H), 8.36 (d, 2H), 8.45 (d, 1H), 9.52 (s, 1H), 11.31(s, 1H), 12.45 (s, 1H).

EXAMPLE 12 1-Methyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 253-254° C.

¹H-NMR (d₆-DMSO): δ=3.25 (s, 3H), 7.59-7.67 (m, 4H), 8.38 (d, 2H), 8.46(d, 1H), 9.52 (s, 1H), 11.31 (s, 1H), 12.10 (s, 1H).

EXAMPLE 13 1-Benzyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 232-233° C.

¹H-NMR (d₆-DMSO): δ=4.96 (m, 2H), 7.37-7.48 (m, 3H), 7.54-7.67 (m, 6H),8.32 (d, 2H), 8.47 (d, 1H), 9.52 (s, 1H), 11.43 (s, 1H), 12.91 (s, 1H).

EXAMPLE 141-(4-Fluorophenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 225-226° C.

¹H-NMR (d₆-DMSO): δ=7.33 (m, 2H), 7.57-7.65 (m, 3H), 7.70-7.81 (m, 3H),8.34 (d, 2H), 8.54 (d, 1H), 9.57 (s, 1H), 11.62 (s, 1H).

EXAMPLE 15 1-Cyclohexyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 230-232° C.

¹HNMR (d₆-DMSO): δ=1.50-1.75 (m, 6H), 1.80-2.00 (m, 4H), 7.55-7.70 (m,4H), 8.37 (d, 2H), 8.45 (d, 1H), 9.55 (s, 1H), 11.20 (s, 1H), 12.80 (s,1H).

EXAMPLE 16 1-Isopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 229-230° C. 1H NMR (d₆-DMSO): δ=1.40 (d, 6H), 4.40-4.50 (m, 1H),7.58-7.66 (m, 4H), 8.36 (d, 2H), 8.44 (d, 1H), 9.52 (s, 1H), 11.20 (s,1H), 12.48 (s, 1H).

EXAMPLE 171-Furan-2-ylmethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea

m.p.: 250° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.95 (s, 2H), 6.55 (m, 1H), 6.68 (d, 1H), 7.59-7.68(m, 4H), 7.74 (d, 1H), 8.37 (d, 2H), 8.48 (d, 1H), 9.55 (s, 1H), 11.45(s, 1H), 12.83 (s, 1H).

EXAMPLE 181-Methyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 270° C.

¹H NMR (d₆-DMSO): δ=3.25 (s, 3H), 7.70 (d, 1H), 8.44 (d, 2H), 8.50 (d,1H), 8.64 (d, 2H), 9.64 (s, 1H), 11.38 (s, 1H), 12.03 (s, 1H).

EXAMPLE 191-[3-(4-Hydroxyphenyl)pyrido[2,3-]pyrazin-6-yl]-3-methylthiourea

m.p.: 282° C.

¹H NMR (d₆-DMSO): δ=3.25 (s, 3H), 6.98 (d, 2H), 7.57 (d, 1H), 8.26 (d,2H), 8.40 (d, 1H), 9.45 (s, 1H), 10.18 (s, 1H), 11.25 (s, 1H), 12.10 (s,1H).

EXAMPLE 201-Allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 244° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.40 (s, 2H), 5.36 (d, 1H), 5.59 (d, 1H), 6.08-6.15(m, 1H), 7.71 (d, 1H), 8.46 (d, 2H), 8.51 (d, 1H), 8.60 (d, 2H), 9.64(s, 1H), 11.45 (s, 1H), 12.51 (t, 1H).

EXAMPLE 21 Ethyl4-[6-(3-allylthiourea)pyrido[2,3-b]pyrazin-3-yl]benzoate

m.p.: 223-224° C.

¹H NMR (d₆-DMSO): δ=1.39 (t, 3H), 4.35-4.42 (m, 4H), 5.35 (d, 1H), 5.60(d, 1H), 6.08-6.15 (m, 1H), 7.68 (d, 1H), 8.17 (d, 2H), 8.47 (d, 2H),8.50 (d, 9.60 (s, 1H), 11.40 (s, 1H), 12.52 (t, 1H).

EXAMPLE 221-Allyl-3-[3-(3-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 205° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.41 (s, 2H), 5.33 (d, 1H), 5.58 (d, 1H), 6.07-6.15(m, 1H), 6.99 (d, 1H), 7.42 (t, 1H), 7.64 (d, 1H), 7.72 (s, 1H), 7.77(d, 1H), 8.46 (d, 1H), 9.45 (s, 1H), 9.80 (s, 1H), 11.37 (s, 1H), 12.55(s, 1H).

EXAMPLE 231-Allyl-3-(3-benzo[1,3]-dioxol-5-ylpyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 218-220° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.40 (s, 2H), 5.31 (d, 1H), 5.60 (d, 1H), 6.08-6.20(m, 3H), 7.16 (d, 1H), 7.61 (d, 1H), 7.90 (s, 1H), 7.96 (d, 1H), 8.43(d, 1H), 9.49 (s, 1H), 11.34 (s, 1H), 12.58 (s, 1H).

EXAMPLE 241-[3-(4-Hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-prop-2-ynylthiourea

m.p.: 350° C. (decomp.)

¹H NMR (d₆-DMSO): δ=2.09 (s, 1H), 2.44 (s, 2H), 6.99 (d, 2H), 7.19 (s,1H), 7.44 (s, 1H), 8.24 (d, 2H), 8.26 (d, 1H), 9.29 (s, 1H), 10.08 (s,1H), 11.81 (s, 1H).

EXAMPLE 251-Allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 230° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.40 (s, 2H), 5.34 (d, 1H), 5.60 (d, 1H), 6.07-6.15(m, 1H), 6.98 (d, 2H), 7.58 (d, 1H), 8.24 (d, 2H), 8.42 (d, 1H), 9.45(s, 1H), 10.19 (s, 1H), 11.34 (s, 1H), 12.60 (s, 1H).

EXAMPLE 261-[3-(4-Hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(propenyl)thiourea

m.p.:

¹H NMR (d₆-DMSO): δ=2.12 (d, 3H), 5.17 (m, 1H), 6.96 (d, 2H), 7.22-7.26(m, 1H), 7.59 (d, 1H), 8.25 (d, 2H), 8.45 (d, 1H), 9.48 (s, 1H), 10.20(s, 1H), 11.56 (s, 1H), 14.67 (s, 1H).

EXAMPLE 271-Allyl-3-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 270° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.40 (s, 2H), 5.25 (d, 1H), 5.50 (d, 1H), 6.02-6.13(m, 1H), 6.74 (d, 2H), 6.76 (d, 2H), 7.31 (d, 2H), 7.36 (d, 2H), 7.62(d, 1H), 8.42 (d, 1H), 9.78 (s, 1H), 9.85 (s, 1H), 11.30 (s, 1H), 12.47(s, 1H).

EXAMPLE 281-[2,3-Bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(propenyl)thiourea

m.p.: 240° C. (decomp.)

¹H NMR (d₆-DMSO): δ=2.05 (d, 3H), 5.10-5.18 (m, 1H), 6.74 (d, 2H), 6.76(d, 2H), 7.20-7.26 (m, 1H), 7.34 (d, 2H), 7.39 (d, 2H), 7.63 (d, 1H),8.45 (d, 1H), 9.79 (s, 1H), 9.89 (s, 1H), 11.55 (s, 1H), 14.56 (d, 1H).

EXAMPLE 291-Allyl-3-[2-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea

m.p.: 260° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.40 (s, 2H), 5.28 (d, 1H), 5.48 (d, 1H), 6.03-6.12(m, 1H), 6.96 (d, 2H), 7.66 (d, 1H), 8.16 (d, 2H), 8.43 (d, 1H), 9.52(s, 1H), 10.06 (s, 1H), 11.31 (s, 1H), 12.40 (s, 1H).

EXAMPLE 301-Allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-7-yl]thiourea

m.p.: 250° C. (decomp.)

¹H NMR (d₆-DMSO): δ=4.23 (s, 2H), 5.19 (d, 1H), 5.29 (d, 1H), 5.90-6.00(m, 1H), 8.46 (d, 2H), 8.55 (s, 1H), 8.64 (d, 2H), 8.92 (s, 1H), 9.23(s, 1H), 9.77 (s, 1H), 10.35 (s, 1H).

EXAMPLE 31 1-Cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea

m.p.: 158-160° C.

¹H NMR (d₆-DMSO): δ=0.52-0.60 (m, 2H), 0.72-0.82 (m, 2H), 2.70-2.79 (m,1H), 7.57-7.65 (m, 3H), 7.71 (d, 1H), 8.34 (d, 2H), 8.38 (d, 1H), 9.21(s, 1H), 9.46 (s, 1H), 10.12 (s, 1H).

EXAMPLE 32 1-Allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]urea

m.p.: 240° C. (decomp.)

¹H NMR (d₆-DMSO): δ=3.98 (s, 2H), 5.19 (d, 1H), 5.37 (d, 1H), 5.96-6.05(m, 1H), 6.97 (d, 2H), 7.59 (d, 1H), 8.22 (d, 2H), 8.33 (d, 1H), 9.38(s, 1H), 9.45 (s, 1H), 10. 13 (s, 1H), 10. 18 (s, 1H).

EXAMPLE 33 1-(3-Phenylpyrido[2,3-b]pyrazin-6-yl)-3-p-tolylurea

m.p.: 298-299° C.

¹H-NMR (d₆-DMSO): δ=2.29 (s, 3H), 7.20 (d, 2H), 7.52 (d, 2H), 7.59-7.67(m, 3H), 7.80 (d, 1H), 8.38 (d, 2H), 8.44 (d, 1H), 9.59 (s, 1H), 10.36(s, 1H), 11.46 (s, 1H).

EXAMPLE 341-(4-Chloro-3-trifluoromethylphenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea

m.p.: 250° C.

¹H-NMR (d₆-DMSO): δ=7.58-7.67 (m, 3H), 7.74 (d, 1H), 7.80 (d, 1H), 7.87(d, 1H), 8.21 (s, 1H), 8.39 (d, 2H), 8.48 (d, 1H), 9.53 (s, 1H), 10.55(s, 1H), 11.82 (s, 1H).

EXAMPLE 351-(2-Morpholin-4-ylethyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea

m.p.: 226° C.

¹H-NMR (d₆-DMSO): δ=2.45-2.67 (m, 6H), 3.40-3.48 (m, 2H), 3.60-3.69 (m,4H), 7.55-7.70 (m, 4H), 8.30-8.40 (m, 3H), 9.29 (s, 1H), 9.42 (s, 1H),10.18 (s, 1H).

EXAMPLE 36 1-Phenethyl-3-(3-phenylpyrido[2,3-]pyrazin-6-yl)urea

m.p. 250° C. (decomp.)

¹H NMR (d₆-DMSO): δ=2.88-2.95 (m, 2H), 3.52-3.60 (m, 2H), 7.18 (t, 1H),7.28 (t, 2H), 7.42 (d, 2H), 7.58-7.68 (m, 4H), 8.37 (d, 3H), 9.25 (s,1H), 9.48 (s, 1H), 10.18 (s, 1H).

EXAMPLE 37 1-(2,3-Dipyridin-2-ylpyrido[2,3-b]pyrazin-6-yl)-3-ethylurea

m.p.: 236-237° C.

¹HNMR (d₆-DMSO): δ=1.13-1.22 (m, 3H), 3.28-3.39 (m, 2H), 3.60-3.69 (m,4H), 7.31-7.39 (m, 2H), 7.79 (d, 1H), 7.91-7.99 (m, 4H), 8.26 (d, 1H),8.29 (d, 1H), 8.47 (d, 1H), 9.08 (s, 1H), 10.20 (s, 1H).

EXAMPLE 38 1-(2,3-Dimethylpyrido[2,3-b]pyrazin-6-yl)-3-ethylurea

m.p. 246-248° C.

¹H NMR (d₆-DMSO): δ=1.17 (t, 3H), 2.64 (s, 3H), 2.67 (s, 3H), 3.24-3.40(m, 2H), 7.55 (d, 1H), 8.24 (d, 1H), 9.14 (s, 1H), 9.91 (s, 1H).

TABLE 1

Ex. R1 R2 R3 R4 R5 1 Ph H Y = S H —CH₂CH═CH₂ 2 2-naphthyl H Y = S H—CH₂CH═CH₂ 3 4-MeO—Ph H Y = S H —CH₂CH═CH₂ 4 4-HO—Ph H Y = S H—CH₂CH═CH₂, HCl salt 5 Ph H Y = S H —CH₂C(CH₃)═CH₂ 6 2-naphthyl H Y = SH —CH₂C(CH₃)═CH₂ 7 4-MeO—Ph H Y = S H —CH₂C(CH₃)═CH₂ 8 2-naphthyl H Y =S H —Ph-p-NO₂ 9 4-MeO—Ph H Y = S H —Ph-p-NO₂ 10 Ph H Y = S H —C(CH₃)₃ 11Ph H Y = S H cyclopropyl 12 Ph H Y = S H —CH₃ 13 Ph H Y = S H -benzyl 14Ph H Y = S H —Ph-p-F 15 Ph H Y = S H -cyclohexyl 16 Ph H Y = S H—CH(CH₃)₂ 17 Ph H Y = S H -1-furan-2-ylmethyl 18 4-NO₂—Ph H Y = S H —CH₃19 4-HO—Ph H Y = S H —CH₃ 20 4-NO₂—Ph H Y = S H —CH₂CH═CH₂ 21 4-CO₂Et—PhH Y = S H —CH₂CH═CH₂ 22 3-HO—Ph H Y = S H —CH₂CH═CH₂ 233-benzo[1,3]-dioxol-5-yl H Y = S H —CH₂CH═CH₂ 24 4-HO—Ph H Y = S H-propin-2-yl 25 4-HO—Ph H Y = S H —CH₂CH═CH₂ 26 4-HO—Ph H Y = S H—CH═CHCH₃ 27 4-HO—Ph 4-HO—Ph Y = S H —CH₂CH═CH₂ 28 4-HO—Ph 4-HO—Ph Y = SH —CH═CHCH₃ 29 H 4-HO—Ph Y = S H —CH₂CH═CH₂ 30 4-NO₂—Ph H H Y = S—CH₂CH═CH₂ 31 Ph H Y = O H -cyclopropyl 32 4-HO—Ph H Y = O H —CH₂CH═CH₂33 Ph H Y = O H -p-tolyl 34 Ph H Y = O H —Ph-p-Cl-m-CF₃ 35 Ph H Y = O H—CH₂CH₂- morpholin-4-yl 36 Ph H Y = O H -phenethyl 37 2-pyridinyl2-pyri-dinyl Y = O H -ethyl 38 methyl methyl Y = O H -ethylBiological Effects of the Compounds of the Invention

The inhibitory effect on the following human serine/threonine andtyrosine kinases of the compounds of the invention was tested inconventional kinase assays: PKB/Akt1, c-Raf-Mek-Erk, B-Raf-Mek-Erk,Mek-Erk, MAPKs, PDGFRbeta, Flt-3, c-Kit, c-Abl , KDR, FGFR1 and IGF1R.Both the full-length kinases and truncated fragments—but at least thecytoplasmic kinase domains—were employed. The kinases were prepared asrecombinant fusion proteins with GST (glutathion S-transferase) or HISTag in Sf9 cell culture. Depending on the substrate type, the variouskinase reactions were carried out in sandwich ELISA formates or by meansof a simple substrate adsorption assay on 96-well Flashplates (PerkinElmer).

The testing on substances on the c-Raf-Mek-Erk cascade is described indetail below. Selected test results for the c-Raf-Mek-Erk assays arethen listed.

Procedure: c-Raf-Mek-Erk ELISA

Potential inhibitors were firstly investigated at a concentration of 20μg/ml in initial single-dose determinations on 96-well microtiter plates(MTPs). Substances with >70% inhibition were employed for dose-responsestudies.

Reconstitution of the c-Raf-Mek-Erk cascade was quantified with the aidof a cell-free ELISA. The following recombinant prepared kinase proteinswere used: 1.) constitutively active GST-c-Raf-DD from Sf9 cells, 2.)inactive GST-Mek1 from E. coli and 3.) inactive His-Erk2 from E. coli.

A typical kinase assay was carried out in a final volume of 50 μl within each case 20-150 ng of Raf, Mek, Erk protein, 1 mM ATP, 10 mM MgCl₂,150 mM NaCl, 25 mM beta-glycerophosphate, 25 mM Hepes pH 7.5. Before thekinase reaction, the test substances were each preincubated singly witheach of the three kinase proteins at room temperature for 30 minutes.For the kinase reaction, the kinases preincubated with test substancewere combined and incubated at 26° C. for 30 minutes. The reaction wasstopped by a final concentration of 2% SDS and 10 minutes at 50° C. in aheafing block.

For the immunodetection, the reaction mixtures were transferred to96-well MTPs coated with anti-Erk Ab(K-23, Santa Cruz Biotechnology,incubated at room temperature for 60 minutes and washed 3× with TBST.Anti-phospho-Erk Ab (#9106, New England Biolabs) 1:500 in 50 μl ofTBST/1% BSA, was added and incubated at 4° C. overnight. After the MTPshad been washed 3× with TBST, secondary anti-mouse IgGPOD conjugate(#NA931, Pharmacia) 1:2500 was added, incubated at room temperature for1 h and again washed 3× with TBST. For colorimetric detection of thekinase reaction, 50 μl of OPD (o-phenyldiamine dihydrochloride)chromogen buffer were pipetted into each of the wells and incubated at37° C. for 30 minutes. The colour reaction was then determined in anELISA reader at 492 nm.

The experimental determination of dose-response plots took place usingthe same experimental design with 10 semilogarithmically gradedconcentrations from 31.6 pM-100 μM. The IC₅₀ values were calculated inGraphPadPrism.

The compounds of the invention show effective inhibition of Erkphosphorylation with IC₅₀ values ranging to 400 μM (see exemplaryembodiments 4 and 12).

Exemplary embodiment IC₅₀ (μM) 1   ca. 1.0 2  16 3   ca. 1.0 4    0.4 5  ca. 1.0 6 ca. 100   7  43 8 >100 9 >100 10 >100 11    0.9 12    0.413 >100 14 ca. 50  33 >100 34 >100 35  15

1. A pyrido[2,3-b]pyrazine compound of general Formula I

in which the substituents R1-R4 have the following meaning: R1 and R2are independently of one another: (i) hydrogen, (ii) hydroxyl, (iii)halogen, (iv) allyl, where the alkyl radical is saturated and mayconsist of 1 to 8 C atoms, (v) unsubstituted or substituted aryl, wherethe aryl radical may have one or more identical or different F, Cl, Br,I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl,NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl,NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl,NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl,NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl,S-heteroaryl,OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl,O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,O-alkyl-heteroaryl, O-alkyl-OH, O—(CH₂)_(n)—O, OC(O)-alkyl,OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl,OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl,OSO₂-alkyl-aryl, OSO₂-alkylheteroaryl, OP(O)(OH)₂, C(O)-alkyl,C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl,CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkylheteroaryl, C(O)—NH₂,C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NHheterocyclyl, C(O)NH-aryl,C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl,C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂,C(O)N(cycloalkyl)₂, C(O)N(aryl)₂, C(O)N(heteroaryl₂, SO-alkyl, SO-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SOZNH-alkyl, SO₂NHaryl, SO₂NH-heteroaryl,SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, n is 1, 2 or3, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroarylsubstituents may in turn themselves be substituted, (vi) unsubstitutedor substituted heteroaryl, where the heteroaryl radical may have one ormore identical or different F, Cl, Br, I, CF₃, CN, NH₂, NHalkyl,NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,NHalkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,NH-alkylheteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl,NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl,NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl,NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl,NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl,S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl,O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl,OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl,OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl,OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂,C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl,CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkylCO₂-alkylheterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)—NH₂,C(O)NHalkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl,C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl,C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂,C(O)N(cycloalkyl)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl,SO₂-alkyl, SO₂O-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NHheteroaryl,SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂-aryl, SO₂O-alkylaryl, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and thealkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituents may inturn themselves be substituted, (vii) OR5, where R5 is alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl,alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl,alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can, fortheir part, in turn be substituted, (viii) SR6, where R6 is alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, andthe alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl andheteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl oralkylheteroaryl substituents can, for their part, in turn besubstituted, (ix) NR7R8, where R7 and R8 are, independently of eachother, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkylcyclyl, alkylheterocyclyl, alkylaryl oralkylheteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl,alkylaryl or alkylheteroaryl substituents can, for their part, in turnbe substituted,  or R7 and R8 are together cycloalkyl or heterocyclyl,where the cycloalkyl and heterocyclyl can, for their part, in turn besubstituted; R3 and R4 are, independently of each other, hydrogen orNR9R10 with the proviso that, when R3=NR9R10, R4=H and when R4=NR9R10,R3=H, and R3 and R4 are not both H or NR9R10 at the same time, where R9is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl oralkylheteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl,alkylaryl or alkylheteroaryl substituents can, for their part, in turnbe substituted, and R10 is: A, B, or C, where (A) is: —C(Y)NR11R12,where Y is O, or S and R11 and R12 are independently of one another (i)hydrogen, (ii) unsubstituted or substituted alkyl, where the alkylradical may have one or more identical or different F, Cl, Br, I, CF₃,CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,NH-heteroaryl, NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl,NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl,NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl,NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl,S-aryl, Sheteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl,O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl,O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl,OC(O)-alkyl-heteroaryl, OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl,OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl,OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl,C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl,CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl,CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)—NH2, C(O)NH-alkyl,C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂O-alkyl,SO₂O-aryl, SO₂NH₂, SO₂NH-alkyl, SO2NH-aryl, SO₂NHheteroaryl,SO₂NH-alkyl-aryl, SO₃H, SO₂-alkyl, SO₂O-aryl, SO₂O-alkylaryl,cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, (iii)unsubstituted or substituted cycloalkyl, where the cycloalkyl radicalmay have one or more identical or different F, Cl, Br, I, NH₂, NH-alkyl,NHcycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl,NHalkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl,NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl,NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl,—NHSO₂-alkyl-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl,O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl,OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl, OSO3H, OSO₂-alkyl,OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl,OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, CO₂H, CO₂-alkyl,CO₂-cycloalkyl, CO₂-heterocyclyl, CO2-aryl, CO₂-heteroaryl,CO₂-alkylcycloalkyl, CO₂-alkylhetero-cyclyl, CO₂-alkyl-aryl,CO₂-alkyl-heteroaryl, C(O)-NH₂, C(O)NHaryl, C(O)NH-cycloalkyl,C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, alkyl or aryl substituents, (iv)unsubstituted or substituted heterocyclyl, where the heterocyclylradical may have one or more identical or different OH, O-alkyl, O-aryl,NH₂, NHalkyl, NH-aryl, alkyl, alkyl-aryl or aryl substituents, (v)unsubstituted or substituted aryl, where the aryl radical may have oneor more identical or different F; Cl, Br, I, CF₃, CN, NH₂, NH-alkyl,NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,NH-alkylcycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl,NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl,NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl,NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl,NHSO₂-cycloalkyl, NHSO2-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl,NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl,S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl,O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl,O-alkyl-hetero-cyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH,O—(CH₂)_(n)—O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl,OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl,OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl,OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂,OSO₂-heterocyclyl, OSO2-alkyl-aryl, OSO2-alkyl-heteroaryl, OP(O)(OH)₂,C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO₂-alkyl, CO₂-cycloalkyl,CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,CO₂-alkylheterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)-NH₂,C(O)NHalkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl,C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl,C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂,C(O)N(cycloalkyl)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl,SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkylaryl, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and n is 1, 2or 3, (vi) unsubstituted or substituted heteroaryl, where the heteroarylradical may have one or more identical or different F, Cl, Br, I, CF₃,CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl,NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl,NH-alkyl-aryl, NH-alkylheteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂,NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl,NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl,NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH,S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-aryl,O-heteroaryl, O-alkylcycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl,O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl,OC(O)-aryl, OC(O)-heteroaryl, OC(O)-alkyl-aryl, OC(O)-alkyl-heteroaryl,OSO₃H, OSO₂-alkyl, OSO₂-cycloalkyl, OSO2-heterocyclyl, OSO₂-aryl,OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂,C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H, CO₂-alkyl, CO₂-cycloalkyl,CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl,CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)—NH₂,C(O)NHalkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl,C(O)NH-heteroaryl, C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl,C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂,C(O)N(cycloalkyl)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂NH₂,SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H,SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl substituents, (vii) —C(O)-R17, where R17 is alkyl,aryl, alkenyl, alkynyl or heteroaryl, and the alkyl, alkenyl, alkynyland aryl substituents may in turn themselves be substituted, (viii) orR11 and R12 together are cycloalkyl or heterocyclyl (ix) alkenyl oralkynyl radical, where the alkenyl or the alkynyl radical has 2 to 8 Catoms; (B) is —C(Y)NR13R14, where Y is NH and R13 and R14 areindependently of one another (i) hydrogen, (ii) unsubstituted orsubstituted alkyl, where the alkyl radical may have one or moreidentical or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl,NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl,NHalkyl-heteroaryl, N(alkyl)2, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl,NHSO₂-cycloalkyl, NHSO2-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl,S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl,O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl,O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl,OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl,OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl,CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO2-aryl,CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl,CO₂-alkyl-aryl, CO₂-alkylheteroaryl, C(O)—NH₂, C(O)NH-alkyl,C(O)NH-cycloalkyl, C(O)NHheterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂,SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl,SO₂NH₂, SO₃H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroarylsubstituents, (iii) unsubstituted or substituted cycloalkyl, where thecycloalkyl radical may have one or more identical or different F, Cl,Br, I, NH2, NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH-aryl,NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl)₂,NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl,NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl,O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl,OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, CO₂H,CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,C(O)-NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,C(O)NH-aryl, C(O) NH-heteroaryl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, alkyl or aryl substituents, (iv)unsubstituted or substituted heterocyclyl, where the heterocyclylradical may have one or more identical or different OH, O-alkyl, O-aryl,NH₂, NH-alkyl, NH-aryl, alkyl or aryl substituents, (v) unsubstituted orsubstituted aryl, where the aryl radical may have one or more identicalor different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NHcycloalkyl,NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl,NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂,NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl,NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl,S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl,O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl,O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH,O-(CH₂)_(n)O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl,OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO2-aryl,OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H,CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,CO₂-alkylcycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl,CO₂-alkyl-heteroaryl, C(O)-NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl,C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NHalkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NHaryl, SO₂NH-heteroaryl, SO₃H,SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl substituents, and n is 1, 2 or 3, (vi) unsubstitutedor substituted heteroaryl, where the heteroaryl radical may have one ormore identical or different F, Cl, Br, I, CF₃, CN, NH₂, NHalkyl,NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NHalkyl-aryl,NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl;NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl,NHSO₂-aryl, NHSO₂-heteroaryl, NO2, SH, S-alkyl, S-aryl, OH, OCF₃,O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl,OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl,OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2H,CO2-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,CO₂-alkyl-cycloalkyl, CO₂-alkylheterocyclyl, CO₂-alkyl-aryl,CO₂-alkyl-heteroaryl, C(O)-NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl,C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-hetero-cyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂-alkyl, SO₂-aryl, SO₂NH₂,SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl, SO₂O-aryl,SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroarylsubstituents, (vii) or R13 and R14 together are cycloalkyl orheterocyclyl (viii) alkenyl or alkynyl radical, where the alkenyl or thealkynyl radical has 2 to 8 C atoms; (C) is —C(NR15)R16 where R15 is Hand R16 is (i) unsubstituted or substituted alkyl, where the alkylradical may have one or more identical or different F, Cl, Br, I, CF₃,NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl,NH-alkyl-aryl, NH-alkylheteroaryl, N(alkyl)₂, NHC(O)-alkyl,NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl,NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH,S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃,O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl,OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl,C(O)-aryl, CO₂H,CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl,CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl,CO₂-alkyl-aryl, CO₂-alkylheteroaryl,C(O)-NH₂, C(O)NH-alkyl,C(O)NH-cycloalkyl, C(O)NHheterocyelyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloallcyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,SO₂-aryl, SO₂NH₂, SO₃H, alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl substituents, (ii) unsubstituted or substituted cycloalkyl,where the cycloalkyl radical may have one or more identical or differentF, Cl, Br, I, NH₂, NH-alkyl, NHcycloalkyl, NH-heterocyclyl, NH-aryl,NH-heteroaryl, NH-alkyl-aryl, NHalkyl-heteroaryl, N(alkyl)₂,NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl,NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl,NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl,O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl,OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl,OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, CO₂H,CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,C(O)-NH2, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl,C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)2, alkyl or aryl substituents,(iii) unsubstituted or substituted heterocyclyl, where the heterocyclylradical may have one or more identical or different OH, O-alkyl, O-aryl,NH₂, NH-alkyl, NH-aryl, alkyl or aryl substituents, (iv) unsubstitutedor substituted aryl, where the aryl radical may have one or moreidentical or different F, Cl, Br, I, CF₃, NH₂, NH-alkyl, NH-cycloalkyl,NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl,NH-alkylheterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH2,NHalkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl,NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl,S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl,O-heterocyclyl, Daryl, O-heteroaryl, O-alkyl-cycloalkyl,O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH,O—(CH₂)_(n)—O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl,OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl OSO₂-cycloalkyl, OSO₂-aryl,OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H,CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,CO₂-alkyl-cycloalkyl, CO₂-alkylheterocyclyl, CO₂-alkyl-aryl,CO₂-alkyl-heteroaryl, C(O)—NH₂, C(O)NHalkyl, C(O)NH-cycloalkyl,C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl,SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NHheteroaryl, SO₃H,SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl,aryl or heteroaryl substituents, and is 1, 2 or 3, (v) unsubstituted orsubstituted heteroaryl, where the heteroaryl radical may have one ormore identical or different F, Cl, Br, I, CF₃, NH₂, NH-alkyl,NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl,NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl,NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-aryl, OH, OCF₃,O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl,OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl,OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl,OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H,CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl,CO₂-alkyl-cycloalkyl, CO₂-alkylheterocyclyl, CO₂-alkyl-aryl,CO₂-alkyl-heteroaryl, C(O)—NH₂, C(O)NHalkyl, C(O)NH-cycloalkyl,C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl,C(O)NH-alkyl-cycloalkyl, C(O)NH-alkyl-heterocyclyl, C(O)NH-alkyl-aryl,C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, C(O)N(cycloalkyl)₂,C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂-alkyl, SO₂-aryl, SO₂NH₂,SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl, SO₂O-aryl,SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroarylsubstituents (vi) alkenyl or alkynyl radical, where the alkenyl or thealkynyl radical has 2 to 8 C atoms; and physiologically tolerable salts,hydrates thereof, and where the compound of the general Formula I andthe physiologically tolerable salts and hydrates thereof are present inthe form of their racemates, in the form of their pure enantiomersand/or diastereomers or in the form of their tautomers or in the form ofmixtures of these enantiomers and/or diastereomers.
 2. The compoundaccording to claims 1, wherein (i) R1, R2, R5, R6, R7, R8, R9, R11, R12,R13, R14, R16, and R17independently of one another, are alkenyl radicalsselected from methyl, ethyl , n-propyl, 2-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, andn-octyl; (ii) R5, R6, R7, R8, R9, R11, R12, R13, R14, R16, and R17,independently of one another, are alkenyl radicals selected fromethylenyl (vinyl), propenyl (—CH₂CH═CH₂; —CH═CH—CH₃, —C(═CH₂)—CH₃),butenyl, pentenyl, hexenyl, heptenyl, and octenyl; or (iii) R5, R6, R7,R8, R9, R11, R12, R13, R14, R16, and R17, independently of one another,are alkynyl radicals selected from ethynyl, propynyl (—CH₂—C≡CH,—C≡C—CH₃), butynyl, pentynyl, hexynyl, heptynyl, and octynyl.
 3. Thecompound according to claim 1, wherein R1, R2, R5, R6, R7, R8, R9, R11,R12, R13, R14, R16, R17, (R7 and R8) together, (R11 and R12) together,and (R13 and R14) together, are, independently of one another,heterocyclyl radicals selected from tetrahydrofuryl, tetrahydropyranyl,pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
 4. The compoundaccording to claim 1, wherein R1, R2, R5, R6, R7, R8, R9, R11, R12, R13,R14, R16, R17, (R7 and R8) together, (R11 and R12) together, and (R13and R14) together, are, independently of one another, heteroarylradicals selected from pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl,isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl,phenothiazinyl, and acridinyl.
 5. The compound according to claim 1,which is one of the following compounds:1-allyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea; 1-allyl-3-(3-naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-allyl-3-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea;1-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thioureahydrochloride;1-(2-methylallyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-(2-methylallyl)-3-(3-naphthalen-2-ylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl)-3-(2-methylallyl)thiourea;1-(3-naphthalen-2-ylpyrido[2,3-b]pymzin-6-yl)-3-(4-nitrophenyl)thiourea;1-[3-(4-methoxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitrophenyl)thiourea;1-tert-butyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-methyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-benzyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-(4-fluorophenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-cyclohexyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-isopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-y1)thiourea;1-furan-2-ylmethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-methyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea;1-[3-(4-hydroxyphenyl)pyrido[2,3-]pyrazin-6-yl]-3-methylthiourea;1-allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea; ethyl4-[6-(3-allylthiourea)pyrido[2,3-b]pyrazin-3-yl]benzoate;1-allyl-3-[3-(3-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea;1-allyl-3-(3-benzo[1,3]dioxol-5-ylpyrido[2,3-b]pyrazin-6-yl)thiourea;1-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-prop-2-ynylthiourea;1-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea;1-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(propenyl)thiourea;1-ally3-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea;1-[2,3-bis(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]-3-(propenyl)thiourea;1-allyl-3-[2-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]thiourea;1-allyl-3-[3-(4-nitrophenyl)pyrido[2,3-b]pyrazin-7-yl]thiourea;1-cyclopropyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea;1-allyl-3-[3-(4-hydroxyphenyl)pyrido[2,3-b]pyrazin-6-yl]urea;1-(3-phenylpyrido[2,3-b]pyrazin-6-yl)-3-p-tolylurea;1-(4-chloro-3-trifluoromethylphenyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl-)urea;1-(2-morpholin-4-ylethyl)-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea;1-phenethyl-3-(3-phenylpyrido[2,3-b]pyrazin-6-yl)urea;1-(2,3-dipyridin-2-ylpyrido[2,3-b)pyrazin-6-yl)-3-ethylurea; and1-(2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-3-ethylurea.
 6. Apharmaceutical composition comprising at least one compound according toclaim
 1. 7. The pharmaceutical composition according to claim 6, furthercomprising at least one additional pharmaceutical active ingredientand/or a pharmaceutically acceptable carrier, diluent or otherexcipient.
 8. A process for producing the pharmaceutical compositionaccording to claim 6, comprising combining at least one compoundaccording to claim 1 with one or more pharmaceutically acceptablecarriers, diluents or other excipients.